Imidazopyridines

ABSTRACT

Compounds of formula I wherein one of A and B is a nitrogen atom and the other is CH, and Ar has one of the meanings stated in the specification, are effective bronchial therapeutics and are also useful for treating dermatoses. These compounds are synthesized and formed into medicament compositions. The compounds and resulting medicament compositions are used for treating airway disorders and dermatoses.

This application is the national phase of PCT/EP07/02310, filed on May6, 1997.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel imidazo[4,5-b]- andimidazo[4,5-c]pyridines, which are used in the pharmaceutical industryfor the production of medicaments.

KNOWN TECHNICAL BACKGROUND

European Patent Application EP 22 495 describes 2-(substitutedphenyl)imidazo[4,5-b]pyridines as cardiotonics and hypertensive agents.European Patent Application EP 72 926 describes 2-(substitutedphenyl)imidazo[4,5-b]- and [4,5-c]pyridines having positive inotropicproperties. European Patent Application EP 79 083 describes2-phenylimidazo-[4,5-]pyridines having vasodilating, positive inotropicand platelet aggregation-inhibiting properties and which do not have aninhibitory action on the myocardial phosphodiesterase. German PatentApplication DE 32 24 512 describes, inter alia,2-phenylimidazo-[4,5-b]pyridines for the treatment of cardiacinsufficiency by increasing the contractility of the heart, and forlowering the blood pressure. German Patent Application DE 32 25 386describes 2-naphthylimidazo-[4,5-b]pyridines having positive inotropic,hypotensive and platelet aggregation-inhibiting properties. GermanPatent Application DE 23 61 757 describes 2-(substitutedphenyl)imidazo[4,5-b]pyridines having hypotensive, positive inotropic,platelet aggregation-inhibiting and bleeding time-prolonging properties.

DESCRIPTION OF THE INVENTION

It has now been found that the novel imidazo[4,5-b]- andimidazo[4,5-c]pyridines described in detail in the following havesurprising and particularly advantageous properties.

The invention thus relates to compounds of the formula I (see attachedformula sheet), in which A or B is a nitrogen atom (N) and the otherletter in each case represents the group CH,

Ar represents a heterocycle having the meaning (a) or (b) (see attachedformula sheet), where

R1 is 1-4C-alkoxy or completely or mainly fluorine-substituted1-4C-alkoxy,

R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,

R3 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,

or in which

R2 and R3, together and including the carbon atom to which both arebonded, represent a 3-7C-cycloalkyl radical,

and their tautomeric forms, and the salts of these compounds.

1-4C-Alkoxy is a radical which, beside the oxygen atom, contains astraight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkyl radicals having 1 to 4 carbon atoms which may be mentioned here,for example, are the butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and methyl radicals.

A completely or mainly fluorine-substituted 1-4C-alkoxy which may bementioned, for example, is the 1,2,2-trifluoroethoxy, the2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the2,2,2-trifluoroethoxy and preferably the difluoromethoxy radical.

1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1to 7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl (2-methylhexyl), hexyl, isohexyl, (2-methylpentyl), neohexyl(2,2-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and methyl radicals.

3-7C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl radicals. The 3-5C-cycloalkyl radicalscyclopropyl, cyclobutyl and cyclopentyl may be preferably mentioned.

3-7C-Cycloalkylmethyl represents a methyl radical which is substitutedby one of the abovementioned 3-7C-cycloalkyl radicals. The3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl andcyclopentylmethyl may be preferably mentioned.

Compounds of the formula I to be emphasized are those in which

A or B is a nitrogen atom (N) and the other letter in each caserepresents the group CH,

Ar represents a heterocycle having the meaning (a) or (b), where

R1 is 1-2C-alkoxy or completely or mainly fluorine-substituted1-2C-alkoxy,

R2 is hydrogen, 1-7C-alkyl or 3-5C-cycloalkyl and

R3 is hydrogen, 1-7C-alkyl or 3-5C-cycloalkyl, or

R2 and R3, together and including the carbon atom to which both arebonded, represent a 3-7C-cycloalkyl radical,

and their tautomeric forms, and the salts of these compounds.

Preferred compounds of the formula I are those in which

A or B is a nitrogen atom (N) and the other letter in each caserepresents the group CH,

Ar represents a heterocycle having the meaning (a), where

R1 is 1-2C-alkoxy or completely or mainly fluorine-substituted1-2C-alkoxy,

R2 is hydrogen, 1-4C-alkyl or 3-5C-cycloalkyl and

R3 is hydrogen or 1-4C-alkyl, or

R2 and R3, together and including the carbon atom to which both arebonded, represent a cyclopropyl, cyclobutyl or cyclopentyl ring, or

Ar represents a heterocycle having the meaning (b), where

R1 is 1-2C-alkoxy or completely or mainly fluorine-substituted1-2C-alkoxy,

R2 is 1-4C-alkyl or 3-5C-cycloalkyl and

R3 is hydrogen or 1-4C-alkyl, or

R2 and R3, together and including the carbon atom to which both arebonded, represent a cyclopropyl, cyclobutyl or cyclopentyl ring,

and their tautomeric forms, and the salts of these compounds.

Particularly preferred compounds of the formula I are those in which

A or B is a nitrogen atom (N) and the other letter in each caserepresents the group CH,

Ar represents a heterocycle having the meaning (a), where

R1 is difluoromethoxy or methoxy,

R2 is 1-4C-alkyl and

R3 is 1-4C-alkyl, or

R2 and R3, together and including the carbon atom to which both arebonded, represent a cyclopropyl, cyclobutyl or cyclopentyl ring, or

Ar represents a heterocycle having the meaning (b), where

R1 is difluoromethoxy or methoxy,

R2 and R3, together and including the carbon atom to which both arebonded, represent a cyclopropyl, cyclobutyl or cyclopentyl ring,

and their tautomeric forms, and the salts of these compounds.

Possible salts for compounds of the formula I, depending onsubstitution, are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerable saltsof the inorganic and organic acids customarily used in pharmacy. Thosewhich are suitable are on the one hand water-soluble and water-insolubleacid addition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation--depending on whether it is a mono-or polybasic acid and depending on which salt is desired--in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are also possible. Examples of saltswith bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here also the bases are employedin salt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts which can be initially obtained, forexample, in the preparation of the compounds according to the inventionon an industrial scale as process products, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

The compounds of the formula I are tautomers and--if the substituents R2and R3 are not identical--also chiral compounds. The invention thereforeincludes both the pure tautomers and enantiomers and their mixtures inany mixing ratio, including the racemates. The enantiomers can beseparated (see, for example, WO92/08716) in a manner known per se (forexample by preparation and separation of appropriate diastereoisomericcompounds).

The invention further relates to a process for the preparation of thecompounds of the formula I and their salts. The process comprisescondensing carboxylic acids of the formula II (see attached formulasheet), in which Ar has the meaning indicated above, withdiaminopyridines of the formula III (see attached formula sheet), inwhich A and B have the meanings mentioned above, and if desired thenconverting resulting compounds of the formula I into their salts, or, ifdesired, then converting resulting salts of the compounds of the formulaI into the free compounds.

The condensation is carried out in a manner known per se to the personskilled in the art in the presence of a suitable condensing agent, suchas, for example, phosphorus oxychloride, in a suitable inert solvent,e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclichydrocarbon such as toluene or xylene, or another inert solvent such asacetonitrile, or without further solvent using an excess of condensingagent, preferably at elevated temperature, in particular at the boilingtemperature of the solvent or condensing agent used.

Intermediates of the formulae IVa and/or IVb optionally formed in thecondensation (see attached formula sheet), in which the substituents andsymbols have the abovementioned meanings, can be isolated. The furtherinternal condensation to give corresponding compounds of the formula Iis preferably carried out by treatment with an acid, such as, forexample, p-toluenesulfonic acid in a suitable solvent. Water of reactionformed in this process is expediently removed continuously by azeotropicdistillation.

For example, the reaction is carried out as described in the followingexamples or, for example, as described in European Patent Application EP72 926, in J. Med. Chem. 28 (6) [1985] 717-727 or in Arch. Pharm. 323(8) [1990]501-505.

The isolation and purification of the substances according to theinvention is carried out in a manner known per se, for example bydistilling off the solvent in vacuo and recrystallizing the resultingresidue from a suitable solvent or subjecting it to one of the customarypurification methods, such as, for example, column chromatography onsuitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g. in a chlorinated hydrocarbon, such as methylene chlorideor chloroform, or a low-molecular weight aliphatic alcohol (ethanol,isopropanol), which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically nontolerablesalts can be converted into pharmacologically tolerable salts.

Carboxylic acids of the formula II in which Ar has the meaningsindicated above are accessible from the corresponding compounds of theformula V (see attached formula sheet), in which Z is formyl (CHO) orcyano (CN).

For example, compounds of the formula V in which Z has the meaning ofcyano are hydrolyzed with alkali metal hydroxides (if appropriate usinghydrogen peroxide), or appropriately substituted compounds of theformula V in which Z has the meaning of formyl are oxidized to thecompounds of the formula II (e.g. as described in J. Org. Chem. 1986,51, 569-571).

Diaminopyridines of the formula III are known or can be prepared in aknown manner.

The compounds of the formula V in which Ar represents a heterocyclehaving the meaning (a) (see attached formula sheet) and Z has theabovementioned meanings are accessible by a cesium fluoride-mediatedClaisen rearrangement of the appropriately substituted compounds of theformula VI (see attached formula sheet) (e.g. as described in Chem.Pharm. Bull. 1992, 40(5), 1148-1153 and Chem. Pharm. Bull. 1992, 40(8),2002-2006). In the compounds of the formula VI, R1, R2 and R3 have themeanings indicated above and Z represents cyano or formyl.

The compounds of the formula V in which Ar represents a heterocyclehaving the meaning (b) (see attached formula sheet) and Z has theabovementioned meanings are accessible by a Claisen rearrangement of theappropriately substituted compounds of the formula VI (see attachedformula sheet) (e.g. as described in J. Med. Chem. 1983, 26(11), 1585 orin Chem. Pharm. Bull. 1992, 40(5), 1148-1153 and literature citedthere). In the compounds of the formula VI, R1, R2 and R3 have themeanings indicated above and Z represents cyano or formyl.

The compounds of the formula V in which Ar represents a heterocyclehaving the meaning (a) or (b) and Z is cyano can be obtained from theappropriately substituted compounds of the formula V in which Z isformyl by reaction with hydroxylamine in formic acid (e.g. as describedin Synthesis 1979, 2, 112-113).

The compounds of the formula VI are either known or can be prepared in amanner known to the person skilled in the art, such as described, forexample, in Tetrahedron Lett. 1994, 35, 6405-6408.

The following examples serve to illustrate the invention in greaterdetail without restricting it. Likewise, further compounds of theformula I whose preparation is not explicitly described can be preparedin an analogous manner or in a manner familiar per se to the personskilled in the art using customary process techniques.

In the examples, m.p. represents melting point, b.p. boiling point, hhour(s), RT room temperature, EF empirical formula, MW molecular weight,Calc. calculated. The compounds and their salts mentioned in theexamples are a preferred subject of the invention.

EXAMPLES

Final products

1. 2-[7-Methoxy-2-(1-methylethyl)benzofuran-4-yl]imidazo[4,5-b]pyridine

4.6 g of 7-methoxy-2-(1-methylethyl)benzofuran-4-carboxylic acid and 2.2g of 2,3-diaminopyridine are boiled under reflux for 4 h in 80 ml ofphosphorus oxychloride. The mixture is largely evaporated in vacuo, theresidue is partitioned between 100 ml of ice water and 500 ml of ethylacetate and the aqueous phase is rendered alkaline with 50 percentsodium hydroxide solution. The organic phase is separated off, theaqueous phase is extracted a further two times by shaking with ethylacetate, and the organic phases are combined, dried over ignited calciumcarbonate and concentrated in vacuo. The residue is chromatographed onsilica gel using a 1:1 mixture of toluene and ethyl acetate. After theevaporation of appropriate fractions, 1.7 g (28.3% of theory) of titlecompound having the m.p. 242° C. are obtained.

EF: C₁₈ H₁₇ N₃ O₂, MW: 307.34

Elemental analysis: Calc.: C, 70.34; H, 5.58; N, 13.67; Found: C, 70.23;H, 5.50; N, 13.58.

Starting from the starting compounds described in the following, thefinal products described in the following are obtained, by reacting theappropriate carboxylic acids of the formula II with appropriatediaminopyridines of the formula III analogously to Example 1:

2.2-[7-Difluoromethoxy-2(1-methylethyl)benzofuran-4yl]imidazo[4,5-b]pyridine

M.p.: 236° C.

EF: C₁₈ H₁₅ F₂ N₃ O₂, MW: 343.32

Elemental analysis: Calc.: C, 62.97; H, 4.40; F, 11.07; N, 12.24; Found:C, 63.07; H, 4.43; F, 11.00; N, 12.08.

3.2-[8-Methoxy-2,2-tetramethylene-1[2H]chromen-5-yl]imidazo[4,5-b]pyridine

M.p.: 258° C.

EF: C₂₀ H₁₉ N₃ O₂, MW: 333.38

Elemental analysis: Calc.: C, 72.05; H, 5.74; N, 12.61; Found: C, 71.88;H, 5.80; N, 12.52.

4. 2-(2Cyclopentyl-7-methoxy-benzofuran-4-yl)imidazo[4,5-c]pyridine

M.p.: 202-204° C.

EF: C₂₀ H₁₉ N₃ O₂, MW: 333.39

Elemental analysis: Calc.: C, 72.05; H, 5.74; N, 12.60; Found: C, 72.03;H, 5.81; N, 12.55.

5.2-[8-Methoxy-2,2-tetramethylene-1[2H]chromen-5-yl]imidazo[4,5-c]pyridine

M.p.: 203-204.5° C.

EF: C₂₀ H₁₉ N₃ O₂, MW: 333.38

Elemental analysis: Calc.: C, 72.05; H, 5.74; N, 12.61; Found: C, 71.65;H, 5.84; N, 12.41.

6.2-[7-Difluoromethoxy-2-(1-methylethyl)benzofuran-4-yl]imidazo[4,5-c]pyridine

1.8 g ofN-(3-aminopyrid-4-yl)-7-difluoromethoxy-2-(1-methylethyl)benzofuran-4carboxamideare boiled with 4.0 g of p-toluenesulfonic acid in 50 ml of toluene for3 h in a water separator. The cooled solution is extracted by shakingwith 50 ml of 2 N sodium hydroxide solution, the separated aqueous phaseis extracted a further two times with 50 ml of ethyl acetate each time,and the organic phases are combined, dried over ignited potassiumcarbonate and concentrated in vacuo. The residue is crystallized fromethanol/water. 1.7 g (100% of theory) of the title compound of m.p. 201°C. are obtained.

EF: C₁₈ H₁₅ F₂ N₃ O₂, MW: 343.32

Elemental analysis: Calc.: C, 62.97; H, 4.40; F, 11.07; N, 12.24; Found:C, 62.76; H, 4.46; F, 11.10; N, 11.92.

Starting from the starting compounds IVa and/or IVb described in thefollowing, the final product described in the following is obtainedanalogously to Example 6:

7. 2-[7-Methoxy-2-1-methylethyl)benzofuran-4-yl]imidazo[4,5-c]pyridine

M.p.: 226° C.

EF: C₁₈ H₁₇ N₃ O₂, MW: 307.34

Elemental analysis: Calc.: C, 70.34; H, 5.58; N, 13.67; Found: C, 70.36;H, 5.61; N, 13.65.

Starting compounds

A.N-3-Aminopyridyl-4)-7-difluoromethoxy-2-(1-methylethyl)benzofuran-4-carboxamide

5.4 g of 7-difluoromethoxy-2-(1-methylethyl)benzofuran-4-carboxylic acidand 2.2 g of 3,4-diaminopyridine are boiled under reflux for 4 h in 80ml of phosphorus oxychloride. The mixture is largely evaporated invacuo, the residue is partitioned between 100 ml of ice water and 500 mlof ethyl acetate and the aqueous phase is rendered alkaline with 50percent sodium hydroxide solution. The organic phase is separated off,the aqueous phase is extracted a further two times by shaking with ethylacetate, and the organic phases are combined, dried over ignitedpotassium carbonate and concentrated in vacuo. The residue ischromatographed on silica gel using a 9:1 mixture of ethyl acetate andmethanol. After the evaporation of appropriate fractions, 2.0 g (29.4%of theory) of the title compound of m.p. 199° C. are obtained.

In the same manner, starting from an appropriate carboxylic acid of theformula It in which Ar represents a heterocycle having the meaning (a)(see attached formula sheet), the compound described in the following isprepared:

B.N-(3-Aminopyridyl-4)-7-methoxy-2-(1-methylethyl)benzofuran-4-carboxamide

M.p.: 236° C.

C. 7-Difluoromethoxy-2(1-methylethyl)benzofuran-4carboxylic acid

A solution of 0.88 g of sodium chlorite in 5 ml of water is addeddropwise to 1.6 g of7-difluoromethoxy-2-(1-methylethyl)benzofuran-4-carbaldehyde and 0.83 gof amidosulfuric acid, dissolved in 15 ml of glacial acetic acid, suchthat the internal temperature is kept between 15 and 20° C. The mixtureis stirred for a further 1 h and then poured into 150 ml of ice water,and the precipitate formed is filtered off with suction and washed withwater until acid-free. For purification, the crude product is dissolvedin halfconcentrated, aqueous ammonia, and the aqueous solution isextracted with toluene and acidified with 2 N hydrochloric acid to pH1-2. The precipitate formed is filtered off with suction, washed withwater until acid-free and dried in vacuo: m.p. 169° C.

In a similar manner, starting from an appropriate carbaldehyde of theformula V in which Ar has the abovementioned meanings and Z is formyl,the following compounds are prepared:

D. 7-Methoxy-2-(1-methylethyl)benzofuran-4-carboxylic acid

M.p.: 166° C.

E. 8-Methoxy-2,2-tetramethylene-1[2H]chromene-5-carboxylic acid

M.p.: 181° C.

F. 7-Methoxy-2-cyclopentylbenzofuran-4-carboxylic acid

0.5 g of 7-methoxy-2-cyclopentylbenzofuran-4carbonitrile is heated toreflux for 5 h in a solution of 10 ml of n-butanol, 30 ml of sodiumhydroxide solution (50% strength) and 2.5 ml of hydrogen peroxide (30%strength). The mixture is then diluted with ice water, acidified to pH1-2 with 2 N hydrochloric acid and the precipitate formed is filteredoff with suction, washed with water until acid-free and dried in vacuo:m.p. 170-171° C.

In a similar manner, starting from an appropriate carbonitrile of theformula V in which Ar represents a heterocycle having the meaning (b)and Z is cyano, the following compound is prepared:

G. 8-Methoxy-2,2-tetramethylene-1[2H]chromene-5-carboxylic acid

M.p.: 180° C.

H. 7-Difluoromethoxy-2-(1-methylethyl)benzofuran-4-carbaldehyde

5.5 g of 4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy) benzaldehyde areheated to reflux with 7.2 g of cesium fluoride with nitrogen aerationfor 12 h in 30 ml of N,N-diethylaniline. The mixture is stirred into 300ml of 4 N hydrochloric acid after cooling, the resulting emulsion isextracted three times with 50 ml of ethyl acetate, and the organicextracts are combined, dried over ignited potassium carbonate andevaporated in vacuo. The residue is chromatographed on silica gel usingtoluene. After the evaporation of the appropriate fractions, the titlecompound is obtained as an oil.

In the same manner, starting from the appropriate benzaldehydes of theformula VI in which Z represents a formyl group, the following compoundsare prepared:

H. 7-Methoxy-2-(1-methylethyl)benzofuran-4-carbaldehyde

Oil.

J. 7-Methoxy-2-cyclopentylbenzofuran-4-carbaldehyde

Oil.

In the same manner, starting from the appropriate benzonitriles of theformula VI in which Z represents a cyano group, the following compoundis prepared:

K. 7-Methoxy-2-1-methylethyl)benzofuran-4-carbonitrile

Oil.

L. 8-Methoxy-2,2-tetramethylene-1[2H]chromene-5-carbaldehyde

1.9 g of 3-(1-ethynylcyclopentyloxy)-4-methoxybenzaldehyde are heated toreflux under nitrogen aeration for 3 h in 10 ml of N,N-diethylaniline.The mixture is stirred into 50 ml of 4 N hydrochloric acid aftercooling, the resulting emulsion is extracted three times with 20 ml ofethyl acetate, and the organic extracts are combined, dried over ignitedpotassium carbonate and evaporated in vacuo. The residue ischromatographed on silica gel using dichloromethane. After theevaporation of the appropriates fractions, the title compound of m.p.71.5-73° C. is obtained.

In the same manner, starting from an appropriate benzonitrile of theformula VI in which Z represents a nitrite group, the following compoundis prepared:

M. 8-Methoxy-2,2-tetramethylene-1[2H]chromene-5-carbonitrile

M.p. 62° C.

N. 2-Cyclopentyl-7-methoxybenzofuran-4-carbonitrile

27.6 g of 2-cyclopentyl-7-methoxybenzofuran-4-carbaldehyde are heated toreflux for 1.5 h with 11.6 g of hydroxylamine and 19.7 g of sodiumformate in 250 ml of formic acid. The cooled solution is stirred inabout 1.5 l of a 1:1 mixture of ice water and ethyl acetate, and theorganic phase is separated off, dried over ignited potassium carbonateand evaporated in vacuo. The residual oil is sufficiently pure forfurther processing.

O. 4-Difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy)benzaldehyde

Solution 1:

19.0 g of 2-methyl-3-butyn-2-ol are dissolved under nitrogen aeration in60 ml of dry acetonitrile, cooled to -5° C. with ice/salt, 22.8 g of1,8-diazabicyclo[5.4.0]undec-7-en (DBU) are added, the mixture isstirred at -5° C. for 10 min. and 24.4 g of trifluoroacetic anhydrideare then added dropwise such that the temperature of the solution iskept below 0° C. After addition is complete, the solution is stirred at-5° to -2° C. for a further 30 min.

Solution 2:

18.1 g of 4-difluoromethoxy-3-hydroxybenzaldehyde are dissolved undernitrogen aeration in 60 ml of dry acetonitrile, cooled to -5° C. withice/salt, 0.01 g of copper(l) chloride and 19.8 g of DBU are added andthe mixture is stirred for a further 30 min. at -5° C.

Solution 1 is now added dropwise to Solution 2 with stirring at -5° C.in the course of 40 min. and the mixture is stirred for 5 h at 0° C. Themixture is then evaporated in vacuo, the residue is taken up in 100 mlof water and the mixture is extracted three times with 200 ml of tolueneeach time. The combined toluene extracts are washed successively withthree times 50 ml of 1 N hydrochloric acid, two times 50 ml of 1 Nsodium hydroxide solution, 50 ml of saturated sodium bicarbonatesolution and finally with 50 ml of saturated sodium chloride solution,dried over ignited magnesium sulfate, concentrated in vacuo andchromatographed on silica gel using a mixture of cyclohexane/ethanol(97:3). After evaporation of the appropriate fractions,4-difluoromethoxy-3-(2-methyl-3-butyn-2-yloxy)benzaldehyde is obtainedas an oil.

In the same manner, corresponding to example O.,3-hydroxy-4-methoxybenzaldehyde is reacted with appropriate 1-ethynylalcohols:

P. 3-(2-Methyl-3-butyn-2-yloxy)-4-methoxybenzaldehyde

Oil.

Q. 3-(1-Ethynylcyclopentyloxy)-4-methoxybenzaldehyde

M.p. 91.5-93° C.

In the same manner, corresponding to example O., the followingbenzonitriles of the formula VI in which Z represents a cyano group areprepared from 3-hydroxy-4-methoxybenzonitrile:

R. 3-(1,1-Dimethylprop-2-in-1-yloxy)-4-methoxy-benzonitrile

M.p. 103° C.

S. 3-(1-Ethynylcyclopentyloxy)-4-methoxybenzonitrile

M.p. 67° C.

Commercial Utility

The compounds according to the invention have useful pharmacologicalproperties which make them commercially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (namely of type IV), theyare suitable on the one hand as bronchial therapeutics (for thetreatment of airway obstructions on account of their dilating but alsoon account of their respiratory rate- or respiratory drive-increasingaction) and for the elimination of erectile dysfunction on account ofthe vasodilating action, but on the other hand especially for thetreatment of disorders, in particular of inflammatory nature. e.g. ofthe airways (asthma prophylaxis), of the skin, of the intestine, of theeyes and of the joints, which are mediated by mediators such ashistamine, PAF (platelet-activating factor), arachidonic acidderivatives such as leukotrienes and prostaglandins, cytokines,interleukins, chemokines, alpha-, beta- and gamma-interferon, tumornecrosis factor (TNF) or oxygen radicals and proteases. In this context,the compounds according to the invention are distinguished by a lowtoxicity, a good enteral absorption (high bioavailability), a largetherapeutic width and the absence of appreciable side effects.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed in human and veterinary medicine astherapeutics, where they can be used, for example, for the treatment andprophylaxis of the following illnesses: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of varying origins(bronchitis, allergic bronchitis, bronchial asthma); dermatoses(especially of proliferative, inflammatory and allergic nature) such as,for example, psoriasis (vulgaris), toxic and allergic contact eczema,atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus inthe anogenital region, alopecia areata, hypertrophic scars, discoidlupus erythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, and other proliferative, inflammatory andallergic skin disorders; disorders which are based on an excessiverelease of TNF and leukotrienes, e.g. disorders of the arthritis type(rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and otherarthritic conditions), disorders of the immune system (AIDS, multiplesclerosis), shock symptoms [septic shock, endotoxin shock, gram-negativesepsis, toxic shock syndrome and ARDS (adult respiratory distresssyndrome)], and generalized inflammations in the gastrointestinal region(Crohn's disease and ulcerative colitis); disorders which are based onallergic and/or chronic, faulty immunological reactions in the region ofthe upper airways (pharynx, nose) and the adjacent regions (paranasalsinuses, eyes), such as, for example, allergic rhinitis/sinusitis,chronic rhinitis/sinusitis, allergic conjunctivitis and nasal polyps;but also disorders of the heart which can be treated by PDE inhibitors,such as, for example, cardiac insufficiency, or disorders which can betreated on account of the tissue-relaxing action of the POE inhibitors,such as, for example, erectile dysfunction or colics of the kidneys andof the ureters in connection with kidney stones.

The invention further relates to a process for the treatment of mammals,including humans, which are suffering from one of the abovementioneddiseases. The process comprises administering to the sick mammal atherapeutically active and pharmacologically tolerable amount of one ormore of the compounds according to the invention.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of the diseasesmentioned.

The invention likewise relates to the use of the compounds according tothe invention for the production of medicaments which are employed forthe treatment and/or prophylaxis of the diseases mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the diseases mentioned, which contain one or moreof the compounds according to the invention.

The medicaments are prepared by processes which are known per se andfamiliar to the person skilled in the art. As medicaments, the compoundsaccording to the invention (=active compounds) are used either as such,or preferably in combination with suitable pharmaceutical auxiliaries,e.g. in the form of tablets, coated tablets, capsules, suppositories,plasters, emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95%.

The person skilled in the art is familiar on account of his expertknowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulations. Beside solvents, gel-forming agents,ointment bases and other active compound excipients, it is possible touse, for example, antioxidants, dispersants, emulsifiers, preservatives,solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. To this end, these are either administered directly aspowders (preferably in micronized form) or by atomizing solutions orsuspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean Patent 163 965.

For the treatment of dermatoses, the administration of the compoundsaccording to the invention takes place, in particular, in the form ofthose medicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and processed further to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations which may bementioned are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by methods knownper se. The dosage of the active compounds is carried out in the orderof magnitude customary for PDE inhibitors. Thus topical applicationforms (such as, for example, ointments) for the treatment of dermatosescontain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarilybetween 0.01 and 0.5 mg/kg. The customary dose in the case of systemictherapy is between 0.05 and 2 mg per day.

Biological Investigations

In the investigation of PDE IV inhibition at the cellular level, theactivation of inflammatory cells is ascribed particular importance. Anexample which may be mentioned is the FMLP(N-formyl-methionyl-leucyl-phenylalanine)-induced superoxide productionof neutrophilic granulocytes, which can be measured asluminol-potentiated chemoluminescence. [Mc Phail L C, Strum S L, Leone PA and Sozzani S. The neutrophil respiratory burst mechanism. In"Immunology Series" 1992, 57, 47-76; ed. Coffey R G (Marcel Decker,Inc., New York-Basle-Hong Kong)].

Substances which inhibit the chemoluminescence and the cytokinesecretion and the secretion of proinflammatory mediators of inflammatorycells, in particular neutrophilic and eosinophilic granulocytes, arethose which inhibit PDE IV. This isoenzyme of the phosphodiesterasefamilies is particularly represented in granulocytes. Its inhibitionleads to the raising of the intracellular cyclic AMP concentration andthus to the inhibition of cellular activation. PDE IV inhibition by thesubstances according to the invention is thus a central indicator of thesuppression of inflammatory processes. (Giembycz M A, Couldisoenzyme-selective phosphodiesterase inhibitors render bronchodilatorytherapy redundant in the treatment of bronchial asthma?. BiochemPharmacol 1992, 43, 2041-2051; Torphy T J et al., Phosphodiesteraseinhibitors: new opportunities for treatment of asthma. Thorax 1991, 46,512-523; Schudt C et al., Zardaverine: a cyclic AMP PDE III/IVinhibitor. In "New Drugs for Asthma Therapy", 379-402, Birkhauser VerlagBasle 1991; Schudt C et al., Influence of selective phosphodiesteraseinhibitors on human neutrophil functions and levels of cAMP and Ca_(i).Naunyn-Schmiedebergs Arch Pharmacol 1991, 344, 682-690; Nielson C P etal., Effects of selective phosphodiesterase inhibitors onpolymorphonuclear leucocyte respiratory burst. J Allergy Clin Immunol1990, 86, 801-808; Schade et al., The specific type III and IVphosphodiesterase inhibitor zardaverine suppress formation of tumornecrosis factor by macrophages. European Journal of Pharmacology 1993,230, 9-14).

1. Inhibition of PDE IV activity

Methodology

The activity test was carried out according to the method of Bauer andSchwabe, which was adapted to microtiter plates (Naunyn-Schmiedeberg'sArch. Pharmacol. 1980 311, 193-198). Here the PDE reaction takes placein the first step. In a second step, the 5'-nucleotide formed is cleavedto the uncharged nucleoside by a 5'-nucleotidase of the snake venom ofOphiophagus hannah (king cobras. In the third step, the nucleoside isseparated from the remaining charged substrate on ion-exchange columns.The columns are eluted with 2 ml of 30 mM ammonium formate (pH 6.0)directly into minivials to which is additionally added 2 ml ofscintillator fluid for counting.

The inhibitory values determined for the compounds according to theinvention can be seen from the following table A, in which the numbersof the compounds correspond to the numbers of the examples.

                  TABLE A                                                         ______________________________________                                        Inhibition of PDE IV activity                                                  Compound      -log IC.sub.50                                                 ______________________________________                                               1       7.41                                                           2                                8.14                                         3                                5.83                                         4                                7.74                                         5                                6.76                                         6                                8.38                                         7                                8.09                                         ______________________________________                                         ##STR1##

I claim:
 1. A compound of the formula I in whichA or B is a nitrogenatom (N) and the other letter in each case represents the group CH, Arrepresents a heterocycle having the meaning (a) or (b) ##STR2## where R1is 1-4C-alkoxy or completely or mainly fluorine-substituted 1-4C-alkoxy,R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R3is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,or inwhich R2 and R3, together with the carbon atom to which both are bonded,represent a 3-7C-cycloalkyl radical, or a tautomeric form, or a saltthereof.
 2. A compound of the formula I as claimed in claim 1, in whichAor B is a nitrogen atom (N) and the other letter in each case representsthe group CH, Ar represents a heterocycle having the meaning (a) or (b),where R1 is 1-2C-alkoxy or completely or mainly fluorine-substituted1-2C-alkoxy, R2 is hydrogen, 1-7C-alkyl or 3-5C-cycloalkyl and R3 ishydrogen, 1-7C-alkyl or 3-5C-cycloalkyl, or R2 and R3, together with thecarbon atom to which both are bonded, represent a 3-7c-cycloalkylradical, or a tautomeric form, or a salt thereof.
 3. A compound of theformula I as claimed in claim 1, in whichA or B is a nitrogen atom (N)and the other letter in each case represents the group CH, Ar representsa heterocycle having the meaning (a), where R1 is 1-2C-alkoxy orcompletely or mainly fluorine-substituted 1-2C-alkoxy, R2 is hydrogen,1-4C-alkyl or 3-5C-cycloalkyl and R3 is hydrogen or 1-4C-alkyl, or R2and R3, together with the carbon atom to which both are bonded,represent a cyclopropyl, cyclobutyl or cyclopentyl ring, or Arrepresents a heterocycle having the meaning (b), where R1 is 1-2C-alkoxyor completely or mainly fluorine-substituted 1-2C-alkoxy, R2 is1-4C-alkyl or 3-5C-cycloalkyl and R3 is hydrogen or 1-4C-alkyl, or R2and R3, together with the carbon atom to which both are bonded,represent a cyclopropyl, cyclobutyl or cyclopentyl ring, or a tautomericform, or a salt thereof.
 4. A compound of the formula I as claimed inclaim 1, in whichA or B is a nitrogen atom (N) and the other letter ineach case represents the group CH, Ar represents a heterocycle havingthe meaning (a), where R1 is difluoromethoxy or methoxy, R2 is1-4C-alkyl and R3 is 1-4C-alkyl, or R2 and R3, together with the carbonatom to which both are bonded, represent a cyclopropyl, cyclobutyl orcyclopentyl ring, or Ar represents a heterocycle having the meaning (b),where R1 is difluoromethoxy or methoxy, R2 and R3, together with thecarbon atom to which both are bonded, represent a cyclopropyl,cyclobutyl or cyclopentyl ring, or a tautomeric form, or a salt thereof.5. A process for the preparation of a compound of formula I as claimedin claim 1 or a salt thereof, which comprises condensing a compound offormula II, in which Ar has the meanings indicated in claim 1, withdiaminopyridines of the formula III, in which A and B have the meaningsindicated in claim 1 ##STR3## and optionally converting the resultingcompound of formula I into its salt, or optionally converting theresulting salt of the compound of formula I into the free compound.
 6. Acompound of formula I as claimed in claim 1 wherein A is a nitrogenatom.
 7. A compound of formula I as claimed in claim 6 wherein Arrepresents a heterocycle having the meaning (a).
 8. A compound offormula I as claimed in claim 6 wherein Ar represents a heterocyclehaving the meaning (b).
 9. A compound of formula I as claimed in claim 1wherein A represents the group CH.
 10. A compound of formula I asclaimed in claim 9 wherein Ar represents a heterocycle having themeaning (a).
 11. A compound of formula I as claimed in claim 9 whereinAr represents a heterocycle having the meaning (b).
 12. A medicamentcomposition comprising an effective amount of a) a compound as claimedin claim 1, a tautomer thereof or a pharmaceutically-acceptable saltthereof and b) a pharmaceutically-acceptable carrier therefor.
 13. Amethod of treating a subject afflicted with an amenable airway disorderor an amenable dermatosis which comprises administering to the subjectin need thereof an effective amount of a compound of claim 1, a tautomerthereof or a pharmaceutically-acceptable salt thereof.
 14. A medicamentcomposition for treating an airway disorder comprising an effectiveamount of a compound as claimed in claim 1, a tautomer thereof or apharmaceutically-acceptable salt thereof and apharmaceutically-acceptable carrier therefor.
 15. A medicamentcomposition for treating a dermatosis comprising an effective amount ofa compound as claimed in claim 1, a tautomer thereof or apharmaceutically-acceptable salt thereof and apharmaceutically-acceptable carrier therefor.